Preparation of aminopyrimidine compounds

ABSTRACT

A 2-(N-methyl-N-methanesulfonylamino)pyrimidine compound of the formula (3): [R is a hydrocarbyl group], is prepared by the steps of: (I) reacting an isobutyrylacetate ester with 4-fluorobenzaldehyde and urea in the presence of a protonic compound and a metal salt; (II) oxidizing the reaction product of the step (I); (III) reacting the oxidation product of the step (II) with an organic sulfonyl halide or an organic sulfonyl anhydride; and (IV) reacting the reaction product of the step (III) with N-methyl-N-methanesulfonamide.

RELATED APPLICATIONS

This is a Divisional Application of U.S. application Ser. No.10/483,430, filed Jan. 12, 2004, now U.S. Pat. No. 7,304,156, which is aU.S. National Phase Application of International Application No.PCT/JP02/07129, filed Jul. 12, 2002, which claims the benefit ofJapanese Patent Application No. 2001-213417, filed Jul. 13, 2001,Japanese Patent Application No. 2001-213418, filed Jul. 13, 2001,Japanese Patent Application No. 2001-310900, filed Oct. 9, 2001,Japanese Patent Application No. 2001-360339, filed Nov. 27, 2001,Japanese Patent Application No. 2002-7015, filed Jan. 16, 2002, andJapanese Patent Application No. 2002-42076, filed Feb. 19, 2002, all ofwhich are herein incorporated by reference in their entireties.

FIELD OF THE INVENTION

The present invention relates to the preparation of aminopyrimidinecompounds having the following formula (8):

[in the formula (8), R is a hydrocarbyl group, and each of R¹ and R²independently is a hydrogen atom, an alkyl group, an alkylsulfonylgroup, or an arylsulfonyl group], more particularly to the preparationof a 2-(N-methyl-N-methanesulfonylamino)pyrimidine compound having thefollowing formula (3):

wherein R represents a hydrocarbyl group.

BACKGROUND OF THE INVENTION

Bioorg. Med. Chem., 5, 437(1997) describes that the2-(N-methyl-N-methanesulfonylamino)pyrimidine compound is employable asan intermediate compound for producing a cholesterol reducing agent(HMG-CoA reductase inhibitor: S-4522) having the following formula:

and which is now generally known as the calcium salt of rosuvastatin orrosuvastatin calcium.

WO 01/04100 describes a process for preparing the2-(N-methyl-N-methanesulfonylamino)pyrimidine compound which comprisesthe steps of:

reacting methyl isobutyrylacetate with 4-fluoro-benzonitrile to producemethyl 2-[l-amino-1-(4-fluoro-phenyl)methylene]-4-methyl-3-oxopentanate;and

reacting the2-[1-amino-1-(4-fluorophenyl)methyl-ene]-4-methyl-3-oxopentanate withN-cyano-N-methyl-methanesulfonamide which is obtained by reactionbetween N-methylmethanesulfonamide and cyanogen chloride, to produce4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(N-methanesulfonyl-N-methylamino)pyrimidine.

It is described that the total yield (based on the amount of methylisobutyrylacetate) is 45.5%.

It appears that the process described in WO 01/04100 is disadvantageousfor the industrial preparation, because the yield is not high and it isnecessary to employ toxic cyanogen chloride as one of the startingcompounds.

Accordingly, it is an object of the invention to provide a novel processfor preparing a 2-(N-methyl-N-methanesulfonylamino)pyrimidine or ananalogous amino-pyrimidine compound thereof, more particularly toprovide a novel process which provides the compound more convenientlyand/or without employing a toxic compound and/or provides the compoundin high yield and/or high purity.

It is another object of the invention to provide a novel process forpreparing a 2-(N-methyl-N-methanesulfonylamino)pyrimidine compound or ananalogous amino-pyrimidine compound thereof which is favorablyemployable in the industrial preparation.

SUMMARY OF THE INVENTION

The present invention resides in a process for preparing a2-(N-methyl-N-methanesulfonylamino)pyrimidine having the formula (3):

[R is a hydrocarbyl group],which comprises the steps of:

reacting a hydroxypyrimidine compound having the formula (1):

in which R is the same as above,with an organic sulfonyl halide having the formula (2):R′SO₂X   (2)in which R′ is a hydrocarbyl group and X is a halogen atom, or anorganic sulfonic anhydride having the formula (2a):(R′SO₂)₂O   (2a)in which R′ is the same as above, and

reacting the resulting reaction product withN-methyl-N-methanesulfonamide.

The invention also resides in a hydroxypyrimidine compound having theabove-identified formula (1).

The invention further resides in a method for preparing ahydroxypyrimidine compound of the formula (1), which comprises oxidizinga dihydropyrimidinone compound having the formula (4):

wherein R is a hydrocarbyl group.

The invention further resides in a dihydropyrimidinone compound havingthe formula (4).

The invention furthermore resides in a method for preparing adihydropyrimidinone compound of the formula (4), which comprisesreacting an isobutyrylacetate ester having the formula (5):

in which R is a hydrocarbyl group,with 4-fluorobenzaldehyde and urea in the presence of a protoniccompound and a metal salt.

The invention furthermore resides in a method for preparing anaminopyrimidine compound having the formula (8):

wherein R is a hydrocarbyl group, and each of R¹ and R² independently ishydrogen atom, an alkyl group, an alkylsulfonyl group, or anarylsulfonyl group,which comprises reacting a 2-substituted pyrimidine compound having theformula (6):

wherein R is the same as above, and X is a halogen atom or an organicsulfonyloxy group,with an amine compound having the formula (7):

wherein each of R¹ and R² is the same as above.

The invention furthermore resides in a halogenopyrimidine compoundhaving the formula (9):

wherein R is a hydrocarbyl group, and Hal is a halogen atom.

The invention furthermore resides in a method for preparing thehalogenopyrimidine compound of the formula (9), which comprises reactinga hydroxypyrimidine compound of the aforementioned formula (1) with ahalogenating agent.

The invention furthermore resides in an organic sulfonyloxypyrimidinecompound having the formula (10):

wherein each of R and R′ independently is a hydrocarbyl group.

The invention furthermore resides in a method for preparing an organicsulfonyloxypyrimidine compound of the formula (10), which comprisesreacting a hydroxypyrimidine compound of the aforementioned formula (1)with an organic sulfonyl halide having the formula (2):R′SO₂X   (2)wherein R′ is a hydrocarbyl group, and X is a halogen atom, or anorganic sulfonic anhydride having the formula (2a):(R′SO₂)₂O   (2a)in which R′ is the same as above.

The invention furthermore resides in a process for preparing a2-(N-methyl-N-methanesulfonylamino)pyrimidine of the formula (3) whichcomprises the steps of:

(I) reacting an isobutyrylacetate ester of the formula (5) with4-fluorobenzaldehyde and urea in the presence of a protonic compound anda metal salt;

(II) oxidizing the reaction product of the step (I);

(III) reacting the oxidation product of the step (II) with an organicsulfonyl halide of the formula (2) or an organic sulfonic anhydride ofthe formula (2a); and

(IV) reacting the reaction product of the step (III) withN-methyl-N-methanesulfonamide.

In the above-mentioned process, the steps (III) and (IV) can be carriedout continuously in the same reaction mixture.

DETAILED DESCRIPTION OF THE INVENTION

The representative process for the preparation of2-(N-methyl-N-methanesulfonylamino)pyrimidine of the formula (3)according to the present invention is schematically illustrated asfollows:

Each step in the above-illustrated reaction scheme is described below inmore detail.

Step (I)

In the step (I), an isobutyrylacetate ester of the following formula(5):

[R is a hydrocarbyl group].is reacted with 4-fluorobenzaldehyde and urea in the presence of aprotonic compound and a metal salt.

The hydrocarbyl group (i.e., hydrocarbon group) represented by R in theformulas of the compounds involved in the reactions of the invention canbe an alkyl group such as methyl, ethyl, propyl, butyl, pentyl, hexyl,heptyl, octyl, nonyl, or decyl, more particularly an alkyl group having1-6 carbon atoms and especially an alkyl group having 1-4 carbon atoms;a cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl; an aralkyl group such as benzyl, phenylethyl, orphenylpropyl; or an aryl group such as phenyl or methylphenyl. Thehydrocarbyl group can take any isomer configurations such as normal,iso, and tertiary. The hydrocarbyl group can have one or moresubstituents, provided that the substituents do not disturb the reactioninvolved.

The protonic compound can be an inorganic acid or its salt such ashydrochloric acid, sulfuric acid, potassium hydrogensulfate, sodiumhydrogen sulfate, nitric acid, or phosphoric acid; an organic sulfonicacid such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid, or p-bromobenzenesulfonic acid; an organiccarboxylic acid such as acetic acid, propionic acid, butyric acid, orbenzoic acid; an alcohol such as methanol, ethanol, or propanol.Preferred are protonic acids such as hydrochloric acid, sulfuric acid,p-toluenesulfonic acid, and acetic acid. Most preferred is sulfuricacid. The protonic compounds can be employed singly or in combination.

The protonic compound can be employed in an amount of, preferably, 0.01to 3 mol., more preferably 0.1 to 1 mol., per one mol. of theisobutyrylacetate ester.

The metal salt employed in the reaction can be copper(I) chloride,copper(II) chloride, copper(II) acetate, iron(II) chloride, iron(III)chloride, aluminum chloride, nickel(II) bromide, tin(IV) chloride,titanium tetrachloride, or magnesium bromide. Preferred are copper(I)chloride, copper(II) chloride, iron(III) chloride and nickel(II)bromide. Most preferred is copper(I) chloride. The metal salts maycontain water of crystallization. The metal salts can be employed singlyor in combination.

The metal salt can be employed in an amount of, preferably, 0.001 to 5mol., more preferably 0.01 to 0.1 mol., per one mol. of theisobutyrylacetate ester.

The 4-fluorobenzaldehyde can be employed in an amount of, preferably,0.5 to 10 mol., more preferably 0.9 to 1.1 mol., per one mol. of theisobutyrylacetate ester.

The urea can be employed in an amount of, preferably, 0.5 to 10 mol.,more preferably 1.5 to 2 mol., per one mol. of the isobutyrylacetateester.

The reaction can be performed in the presence or absence of a solvent.There are no specific limitations with respect to the solvent employed,so far as the solvent does not disturb the desired reaction. Examples ofthe employable solvents include alcohols such as methanol, ethanol,n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol,sec-butyl alcohol, and t-butyl alcohol; ethers such as diethyl ether,diisopropyl ether, tetrahydrofuran, and dimethoxyethane; nitriles suchas acetonitrile, propionitrile, butyronitrile, and isobutyronitrile;halogenated aliphatic hydrocarbons such as dichloromethane,dichloroethane, chloroform, and carbon tetrachloride; aromatichydrocarbons such as benzene, toluene, and xylene; halogenated aromatichydrocarbons such as chlorobenzene; and nitrated aromatic hydrocarbonssuch as nitrobenzene. Preferred are methanol, ethanol, n-propyl alcohol,isopropyl alcohol, n-butyl alcohol, diisopropyl ether, tetrahydrofuran,dimethoxyethane, acetonitrile, butyronitrile, isobutylonitrile,dichloromethane, dichloroethane, chloroform, toluene, xylene, andchlorobenzene. Especially preferred are methanol, ethanol, and isopropylalcohol. The solvents can be employed singly or in combination.

The solvent can be employed in an amount of, preferably 0.1 to 10liters, more preferably 0.3 to 2 liters, per one mole of theisobutyrylacetate ester. The amount may vary depending on homogeneityand dispersability of the reaction mixture.

The reaction can be conducted by reacting the isobutyrylacetate ester,4-fluorobenzaldehyde, and urea, in a solvent in the presence of aprotonic compound and a metal salt under inert gas atmosphere. Thereaction can be carried out at a temperature of, preferably −10 to 200°C., more preferably 30 to 100° C. There are no specific limitations withrespect to the surrounding pressure.

The resulting product of the reaction, that is, a dihydropyrimidinonecompound of the formula (4), can be isolated and purified according tothe conventional procedures such as distillation, crystallization,recrystallization, and column chromatography.

Step (II)

In the step (II), a dihydropyrimidinone compound of the formula (4),that is, the reaction product of the step (I), is oxidized to give ahydroxypyrimidine compound of the formula (1).

The oxidation (or dehydrogenation oxidation) can be performed in variousconventional manners. Preferred is oxidation utilizing nitric acid,because this oxidation procedure is easily carried out and thepost-treatment of the reaction product is easy.

The nitric acid can be employed in an amount of, preferably 1 to 20mol., more preferably 3 to 15 mol., per one mole of thedihydropyrimidinone compound of the formula (4). The nitric acid of aconcentration of, preferably 40 to 80%, more preferably 50 to 70%, canbe preferably employed.

The oxidation can be performed in the presence or absence of a solvent.There are no specific limitations with respect to the solvent employed,so far as the solvent does not disturb the desired reaction. Examples ofthe preferred solvents include carboxylic acids such as acetic acid,propionic acid, and butyric acid. The solvents can be employed singly orin combination.

The solvent can be employed in an amount of, preferably 0.1 to 7 mL,more preferably 0.5 to 3 mL, per 1 g of the dihydropyrimidinonecompound. The amount may vary depending on homogeneity anddispersability of the reaction mixture.

The oxidation can be conducted by reacting the dihydropyrimidinonecompound and nitric acid in a solvent under inert gas atmosphere. Theoxidation can be carried out at a temperature of, preferably −10 to 100°C., more preferably 0 to 50° C. There are no specific limitations withrespect to the surrounding pressure. A reaction initiator such as sodiumnitrite may be incorporated into the reaction system to accelerate theoxidation rate.

The resulting product of the reaction, that is, the hydroxypyrimidinecompound of the formula (1), can be isolated and purified according tothe conventional procedures such as distillation, crystallization,recrystallization, and column chromatography.

Steps (III) and (IV)

In the steps (III) and (IV), a hydroxypyrimidine compound of the formula(1), that is, the reaction product of the step (II), is reacted with anorganic sulfonyl halide of the formula (2):R′SO₂X   (2)or an organic sulfonic anhydride of the formula (2a):(R′SO₂)₂O   (2a)

and

reacting the resulting reaction product withN-methyl-N-methanesulfonamide.

In the formulas (2) and (2a), R′ is a hydrocarbyl group which can haveone or more substituents. Examples of the hydrocarbyl groups includealkyl groups such as methyl, ethyl, propyl, butyl, pentyl, heptyl,octyl, nonyl, and decyl, more particularly an alkyl group having 1-6carbon atoms and especially an alkyl group having 1-4 carbon atoms;fluorinated alkyl groups such as trifluoromethyl, nonafluorobutyl,tridecafluorohexyl, heptadecafluorooctyl, and uncosafluorodecyl;cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl; aralkyl groups such as benzyl, phenylethyl, andphenylpropyl; and aryl groups, including unsubstituted and substitutedphenyl or naphthyl groups, such as phenyl, naphthyl, tolyl, xylyl,mesityl, triisopropylphenyl, methoxyphenyl, chlorophenyl, andnitrophenyl. Thus, the hydrocarbyl group can have one or moresubstituents, provided that the substituents do not disturb the reactioninvolved. The hydrocarbyl group can take any isomer configurations suchas normal, iso, and tertiary. A particularly suitable value for R′ whenit is aryl includes, for example, a phenyl or naphthyl group(particularly phenyl) which is unsubstituted or bears 1, 2 or 3substituents. The substituents may be independently selected from, forexample, alkyl having 1-4 carbon atoms, alkoxy having 1-4 carbon atoms,halogeno, and nitro.

In the formula (2), X is a halogen atom such as fluorine, chlorine,bromine, and iodine.

Examples of the sulfonyl halides include methanesulfonyl fluoride,methanesulfonyl chloride, ethanesulfonyl chloride, 1-propanesulfonylchloride, 2-propanesulfonyl chloride, trifluoromethanesulfonyl fluoride,trifluoromethanesulfonyl chloride, nonafluorobutanesufonyl fluoride,tridecafluorohexanesulfonyl fluoride, heptadecafluorooctanesulfonylfluoride, uncosafluorodecanesulfonyl fluoride, benzenesulfonyl chloride,1-naphthalenesulfonyl chloride, 2-naphthalenesulfonyl chloride,p-toluenesulfonyl fluoride, p-toluenesulfonyl chloride,2,4,6-trimethylbenzenesulfonyl chloride,2,4,6-triisopropylbenzenesulfonyl chloride, p-methoxybenzenesulfonylchloride, p-chlorobenzenesulfonyl chloride, and 2-nitrobenzenesulfonylchloride. Preferred are trifluoromethanesulfonyl fluoride,benzenesulfonyl chloride, 1-naphthalenesulfonyl chloride,2-naphthalenesulfonyl chloride, p-toluenesulfonyl chloride,2,4,6-trimethylbenzenesulfonyl chloride,2,4,6-triisopropylbenzenesulfonyl chloride, p-methoxybenzenesulfonylchloride, and p-chlorobenzenesulfonyl chloride. Particularly preferredare p-toluenesulfonyl chloride, 2,4,6-trimethylbenzenesulfonyl chloride,2,4,6-triisopropylbenzenesulfonyl chloride, and p-methoxybenzenesulfonylchloride.

Examples of the sulfonic anhydrides include methanesulfonic anhydride,trifluoromethanesulfonic anhydride, benzenesulfonic anhydride, andp-toluenesulfonic anhydride. Preferred are trifluoromethanesulfonicanhydride, benzenesulfonic anhydride, and p-toluenesulfonic anhydride.Particularly preferred are trifluoromethanesulfonic anhydride andp-toluenesulfonic anhydride.

The sulfonyl halide or sulfonic anhydride can be employed in an amountof, preferably 0.1 to 20 mol., more preferably 0.5 to 5 mol., mostpreferably 1 to 2 mol., per one mole of the hydroxypyrimidine compound.

In the subsequent step, N-methylmethanesulfonamide can be employed in anamount of, preferably 0.1 to 30 mol., more preferably 1 to 5 mol., perone mol. of the hydroxypyrimidine compound.

The reactions of the steps (III) and (IV) can be preferably performed inthe presence of a base. Examples of the bases include alkali metalcarbonates such as sodium carbonate and potassium carbonate; alkalimetal hydrogencarbonates such as sodium hydrogencarbonate; alkali metalhydroxides such as lithium hydroxide, sodium hydroxide and potassiumhydroxide; alkali metal alkoxides such as sodium methoxide, sodiumt-butoxide, potassium t-butoxide, and sodium t-pentoxide; and tertiaryamines such as triethylamine, triisopropylamine, diisopropylethylamine,and pyridine. Preferred are sodium carbonate, potassium carbonate,potassium t-butoxide, sodium t-pentoxide, triethylamine, and pyridine.Particularly preferred are potassium carbonate, sodium t-pentoxide, andtriethylamine. Most preferred are potassium carbonate and sodiumt-pentoxide. The bases can be employed singly or in combination.

The base can be employed in an amount of, preferably 0.1 to 30 mol.,more preferably 1 to 5 mol., per one mol. of the hydroxypyrimidinecompound. The whole amount of the base can be incorporated in thereaction system before the reaction begins, or the base can beportionwise added to the reaction system after the reaction begins.

The reaction can be performed in the presence or absence of a solvent.There are no specific limitations with respect to the solvent, so far asthe solvent does not disturb the reaction. Examples of the solventsinclude water; ketones such as acetone, methyl ethyl ketone, and diethylketone; ethers such as diethyl ether and tetrahydrofuran; esters such asethyl acetate, propyl acetate, and butyl acetate; nitrites such asacetonitrile and propionitrile; amides such as N,N-dimethylformamide andN-methylpyrrolidone; sulfoxides such as dimethylsulfoxide; ureas such asN,N′-dimethylimidazolinone. Preferred are acetone, tetrahydrofuran,ethyl acetate, butyl acetate, acetonitrile, N,N-dimethylformamide, anddimethylsulfoxide. Particularly preferred are ethyl acetate, butylacetate and acetonitrile. Most preferred are butyl acetate andacetonitrile. The solvents can be employed singly or in combination.

The solvent can be employed in an amount of, preferably 0.01 to 100liters, more preferably 0.5 to 5 liters, per one mole of thehydroxypyrimidine compound. The amount may vary depending on homogeneityand dispersability of the reaction mixture.

The reaction can be performed by reacting the hydroxypyrimidine compoundand the organic sulfonyl halide or sulfonic anhydride in a solvent inthe presence of a base with stirring under inert gas atmosphere. Thebase can be added portionwise. The reaction can be carried out at atemperature of, preferably −30 to 250° C., more preferably 0 to 150° C.There are no specific limitations with respect to the surroundingpressure.

The resulting product of the reaction, that is, the2-(N-methyl-N-methanecarbonsulfonylamino)pyrimidine compound of theformula (3), can be isolated and purified according to the conventionalprocedures such as distillation, crystallization, recrystallization, andcolumn chromatography.

The 2-(N-methyl-N-methanesulfonylamino)pyrimidine compound of theformula (3) and other pyrimidine compounds of the formula (8) can beprepared from a hydroxypyrimidine compound of the formula (1) via a2-substituted pyrimidine compound of the formula (6) in the followingsteps (V) and (VI):

In the formula (8), R has the same meaning as described above, and eachof R¹ and R² independently is a hydrogen atom, an alkyl group, analkylsulfonyl group, or arylsulfonyl group.Step (V)

In the step (V), a hydroxypyrimidine compound of the formula (1) isreacted with a halogenating agent such as a chlorinating agent, anorganic sulfonyl halide of the formula (2):R′SO₂X   (2)in which R′ has the same meaning as above and X is a halogen atom, or anorganic sulfonic anhydride of the formula (2a):(R′SO₂)₂O   (2a)in which R′ has the same meaning as above.

Examples of the halogenating agents include phosphorus oxychloride andthionyl chloride. The halogenating agents can be employed singly or incombination.

The halogenating agent can be employed in an amount of, preferably 0.1to 50 mol., more preferably 1 to 20 mol., most preferably 1.5 to 10mol., per one mol. of the hydroxypyrimidine compound.

Examples of the organic sulfonyl halides and sulfonic anhydrides arethose described hereinbefore.

The organic sulfonyl halide or sulfonic anhydride can be employed in anamount of, preferably 0.1 to 20 mol., more preferably 0.5 to 5 mol.,most preferably 1 to 2 mol., per one mol. of the hydroxypyrimidinecompound.

The reaction can be performed in the presence or absence of a solvent.There are no specific limitations with respect to the solvent, so far asthe solvent does not disturb the reaction. Examples of the solventsinclude aromatic hydrocarbons such as toluene; halogenated aromatichydrocarbons such as chlorobenzene; nitrated hydrocarbons such asnitrobenzene; halogenated aliphatic hydrocarbons such as methylenechloride and 1,2-dichloroethane; amides such as N,N-dimethylformamide;water (not for a halogenating agent); nitriles such as acetonitrile andpropionitrile; carboxylic acid esters such as ethyl acetate, propylacetate, butyl acetate; ketones such as acetone, methyl ethyl ketone,diethyl ketone; and ethers such as diethyl ether and tetrahydrofuran.Preferred are butyl acetate, toluene, methylene chloride, acetonitrile,chlorobenzene, nitrobenzene, and N,N-dimethylformamide. The solvents canbe employed singly or in combination.

The solvent can be employed in the reaction utilizing the halogenatingagent in an amount of, preferably 0.01 to 10 liters, more preferably 0.1to 2 liters, per one mole of the hydroxypyrimidine compound. The amountmay vary depending on homogeneity and dispersability of the reactionmixture.

The solvent can be employed in the reaction utilizing the sulfonylchloride or sulfonic anhydride in an amount of, preferably 0.1 to 50liters, more preferably 0.5 to 2 liters, per one mole of thehydroxypyrimidine compound. The amount may vary depending on homogeneityand dispersability of the reaction mixture.

The reaction can be carried out by reacting the hydroxypyrimidinecompound and the halogenating agent, in a solvent with stirring underinert gas atmosphere. The reaction can be carried out at a temperatureof, preferably 0 to 200° C., more preferably 50 to 120° C. There are nospecific limitations with respect to the surrounding pressure.

The reaction can be carried out by reacting the hydroxypyrimidinecompound and the sulfonyl halide or sulfonyl anhydride in a solvent withstirring under inert gas atmosphere. The reaction can be carried out ata temperature of, preferably −30 to 200° C., more preferably 0 to 50° C.There are no specific limitations with respect to the surroundingpressure.

The resulting product of the reaction, that is, a 2-substitutedpyrimidine compound such as a chloropyrimidine compound or asulfonyloxypyrimidine compound, can be isolated and purified accordingto the conventional procedures such as distillation, crystallization,recrystallization, and column chromatography.

Step (VI)

In the step (VI), the 2-substituted pyrimidine compound, such as achloropyrimidine compound or a sulfonyloxypyrimidine compound preparedin the step (V) is reacted with an amine compound having the formula(7):

wherein each of R¹ and R² is the same as above.

Examples of the groups of R¹ and R² include a hydrogen atom, alkylgroups such as methyl, ethyl, propyl, butyl, pentyl and hexyl;alkylsulfonyl groups such as methanesulfonyl; and arylsulfonyl groupssuch as benzenesulfonyl and p-toluenesulfonyl.

The amine compound can be employed in an amount of, preferably 0.1 to 30mol., more preferably 1 to 5 mol., per one mol. of the 2-substitutedpyrimidine compound.

The reaction is preferably performed in the presence of a base. Examplesof the bases are those described hereinbefore.

The base can be preferably employed in an amount of, preferably 0.1 to30 mol., more preferably 1 to 5 mol., per one mol. of the 2-substitutedpyrimidine compound.

The reaction can be performed in the presence or absence of a solvent.There are no specific limitations with respect to the solvent, so far asthe solvent does not disturb the reaction. Examples of the solventsinclude water; ketones such as acetone, methyl ethyl ketone, and diethylketone; ethers such as diethyl ether and tetrahydrofuran; esters such asethyl acetate, propyl acetate, and butyl acetate; nitriles such asacetonitrile and propionitrile; amides such as N,N-dimethylformamide andN-methylpyrrolidone; sulfoxides such as dimethylsulfoxide; ureas such asN,N′-dimethylimidazolidinone. Preferred are acetone, tetrahydrofuran,ethyl acetate, butyl acetate, acetonitrile, N,N-dimethylformamide, anddimethylsulfoxide. Particularly preferred are ethyl acetate, butylacetate and acetonitrile. The solvents can be employed singly or incombination.

The solvent can be employed in an amount of, preferably 0.01 to 100liters, more preferably 0.5 to 5 liters, per one mole of the2-substituted pyrimidine compound. The amount may vary depending onhomogeneity and dispersability of the reaction mixture.

The reaction can be conducted by reacting the 2-substituted pyrimidinecompound and the amine compound in a solvent in the presence of a basewith stirring under inert gas atmosphere. The reaction can be carriedout at a temperature of, preferably −20 to 250° C., more preferably 25to 150° C. There are no specific limitations with respect to thesurrounding pressure.

The reaction can be conducted in two separate liquid phases in thepresence of a phase transfer catalyst. Examples of the phase transfercatalysts include tetramethylammonium chloride, tetramethylammoniumbromide, tetraethylammonium fluoride, tetraethylammonium chloride,tetraethylammonium bromide, tetrapropylammonium bromide,tetrapropylammonium iodide, tetrabutylammonium fluoride,tetrabutylammonium chloride, tetrabutylammonium bromide,tetrabutylammonium iodide, tetrapentylammonium bromide,tetrahexylammonium bromide, tetraheptylammonium bromide,tetraoctylammonium bromide, benzyldimethyltetradecylammonium chloride,benzyltriethylammonium chloride, phenyltrimethylammonium chloride,phenyltrimethylammonium iodide, and hexadecyltrimethylammonium chloride.Preferred are tetrabutylammonium chloride, tetrabutylammonium bromide,tetrabutylammonium iodided, benzyltriethylammonium chloride, andhexadecyltrimethylammonium chloride. Most preferred aretetrabutylammonium bromide, benzyltriethylanmonium chloride, andhexadecyltrimethylammonium chloride.

The phase transfer catalyst can be employed in an amount of 0.01 to 0.5mol., preferably 0.05 to 0.2 mol., per one mol. of the 2-substitutedpyrimidine compound.

The resulting product of the reaction, that is, a2-(N-methyl-N-methanesulfonylamino)pyrimidine compound of the formula(3) or other aminopyrimidine compounds of formula (8), can be isolatedand purified according to the conventional procedures such asdistillation, crystallization, recrystallization, or columnchromatography.

The present invention is further described by the following non-limitingexamples.

EXAMPLE 1 Preparation of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-3,4-2(1H)-dihydropyrimidinone

In a 500 mL-volume glass flask equipped with a stirrer, a thermometerand a reflux condenser were placed 28.8 g (0.2 mol.) of methylisobutyrylacetate, 24.8 g (0.2 mol.) of 4-fluorobenzaldehyde, 21.0 g(0.35 mol.) of urea, 200 mg (2 mmol.) of copper(I) chloride, 2 mL ofsulfuric acid, and 200 mL of methanol. The content of the flask washeated to 64-65° C. for 24 hours under reflux with stirring, to carryout the reaction. There was precipitated crystalline product. Thecrystalline product was collected on a filter paper and washed withmethanol to obtain 49.7 g of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-3,4-2(1H)-dihydropyrimidinoneas a colorless crystalline product having the below-mentionedcharacteristics. The yield was 85% (based on the amount of methylisobutyrylacetate).

m.p.: 223-225° C.

UV λ_(max) (CH₃CN, nm): 194.3, 278.6

IR (KBr, cm⁻¹): 3296, 3229, 3137, 2963, 1685, 1629, 1504, 1225, 1097.

¹H-NMR (DMSO-d₆, δ (ppm)): 1.14 (6H, dd, J=6.8, 6.9 Hz), 3.52 (3H, s),4.0-4.2 (1H, m), 5.15 (1H, d, J=3.4 Hz), 7.1-7.2 (2H, m), 7.2-7.3 (2H,m), 7.76 (1H, d, J=3.2 Hz), 8.91 (1H, s).

HRMS: 292.1247 (theoretical value (C₁₅H₁₇FN₂O₃(M+)) 292.1223)

EXAMPLE 2 Preparation of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-3,4-2(1H)-dihydropyrimidinone

The procedures of Example 1 were repeated except for replacing 200 mg (2mmol.) of copper(I) chloride with 5.41 g (20 mmol.) of iron(III)chloride.hexahydrate. There was obtained 35.6 g of4-(4-fluorophenyl)-6-isoproply-5-methoxycarbonyl-3,4-2(1H)-dihydropyrimidinone.The yield was 61% (based on the amount of methyl isobutyrylacetate).

EXAMPLE 3 Preparation of4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine

In a 50 mL-volume glass flask equipped with a stirrer and a thermometerwas placed 11 mL (144 mmol.) of nitric acid (60-61%, sp.gr.: 1.38). Tothe nitric acid was slowly added at room temperature 4.00 g (13.7 mmol.)of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-3,4-2(1H)-dihydropyrimidinoneprepared in the same manner as in Example 1, and the mixture wassubjected to reaction for 30 minutes at room temperature. After thereaction was complete, the reaction mixture was neutralized by placingthe mixture in 140 mL of saturated aqueous sodium hydrogen carbonatesolution. The reaction mixture was then extracted with ethyl acetate.The organic liquid portion was separated and concentrated under reducedpressure. The residue was crystallized from toluene. The crystallineproduct was collected on a filter and washed with toluene to obtain 3.64g of4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine asa colorless crystalline product having the below-mentionedcharacteristics. The yield was 92% (based on the amount of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-3,4-2(1H)-dihydropyrimidinone).

m.p.: 193° C. (decomposed)

UV λ_(max) (CH₃CN, nm): 196.6, 243.2, 317.9

IR (KBr, cm⁻¹): 2991, 2887, 1717, 1653, 1589, 1433, 1280, 1223.

¹H-NMR (DMSO-d₆, δ (ppm)): 1.23 (6H, d, J=6.8 Hz), 3.0-3.2 (1H, m), 3.56(3H, s), 7.3-7.4 (2H, m), 7.5-7.6 (2H, m), 12.25 (1H, brs).

HRMS: 290.1054 (theoretical value (C₁₅H₁₅FN₂O₃(M+)) 290.1067)

EXAMPLE 4 Preparation of4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine

In a 50 mL-volume glass flask equipped with a stirrer and a thermometerwere placed 2.92 g (10 mmol.) of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-3,4-2(1H)-dihydropyrimidinoneprepared in the same manner as in Example 1 and 5 mL of acetic acid. Tothe mixture was slowly added 3.74 mL (50 mmol.) of nitric acid (60-61%,sp.gr.: 1.38). To the mixture was further added 0.07 g (1 mmol.) ofsodium nitrite, and the reaction was carried out for one hour at roomtemperature. After the reaction was complete, the reaction mixture wasneutralized by placing the mixture in 50 mL of saturated aqueous sodiumhydrogen carbonate solution. The reaction mixture was then extractedwith ethyl acetate. The organic liquid portion was separated andconcentrated under reduced pressure. The residue was crystallized fromtoluene. The crystalline product was collected on a filter and washedwith toluene to obtain 2.61 g of4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonyl-pyrimidine asa colorless crystalline product. The yield was 90% (based on the amountof4-(4-fluorophenyl)-6-iso-propyl-5-methoxycarbonyl-3,4-2(1H)-dihydropyrimidinone).

EXAMPLE 5 Preparation of4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine

In a 200 mL-volume glass flask equipped with a stirrer and a thermometerwas placed 54.0 g (735 mmol.) of nitric acid (60-61%, sp.gr.: 1.38). Tothe nitric acid was slowly added at room temperature 30.6 g (105 mmol.)of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-3,4-2(1H)-dihydropyrimidinoneprepared in the same manner as in Example 1, and the mixture wassubjected to reaction for 30 minutes at room temperature. After thereaction was complete, the reaction mixture was poured into 162 mL ofwater. The aqueous mixture was neutralized by adding 61 g of aqueoussodium hydroxide solution (48 wt. %) to precipitate a crystallineproduct. The crystalline product was collected by filtration and driedto obtain 27.6 g of4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxy-carbonylpyrimidine asa colorless crystalline product. The yield was 91% (based on the amountof4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-3,4-2(1H)-dihydropyrimidinone).

EXAMPLE 6 Preparation of4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine

In a 2 L-volume glass flask equipped with a stirrer and a thermometerwas placed 323.3 g (3.09 mol.) of nitric acid (60-61%, sp.gr.: 1.38).The concentrated nitric acid was then cooled to 10° C. To the nitricacid was added 2.36 g (34.2 mmol.) of sodium nitrite, and was furtheradded slowly 100 g (342 mmol.) of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-3,4-2(1H)-dihydropyrimidinoneprepared in the same manner as in Example 1. The mixture was subjectedto reaction for 2 hours at a temperature of 10-12° C. After the reactionwas complete, 970 mL of water was poured into the reaction mixture. Theaqueous mixture was then neutralized by adding 257 g of aqueous sodiumhydroxide solution (48 wt. %) to precipitate a crystalline product. Thecrystalline product was collected by filtration and dried to obtain 93.3g of4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine asa colorless crystalline product. The yield was 94% (based on the amountof4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-3,4-2(1H)-dihydropyrimidinone).

EXAMPLE 7 Preparation of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesulfonyl-amino)pyrimidine

In a 200 mL-volume glass flask equipped with a stirrer, a thermometerand a reflux condenser were placed 5.81 g (20 mmol.) of4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine,3.59 g (26 mmol.) of potassium carbonate (available from Asahi GlassWorks, Co., Ltd., Lot No. 1111632, particle size distribution: 75-250μm: 14%, 75 μm pass: 86%), and 40 mL of butyl acetate. To the mixturewas slowly added 4.19 g (22 mmol.) of p-toluenesulfonyl chloride understirring, and the reaction was carried out at 40° C. for 4 hours.Subsequently, the reaction mixture was cooled to room temperature. Tothe cooled reaction mixture were added 2.84 g (26 mmol.) ofN-methylmethanesulfonamide and 4.15 g (30 mmol.) of potassium carbonate(same as above). The mixture was heated to 110-125° C. for 2 hours underrefluxing to carry out a reaction. After the reaction was complete, themixture was cooled to room temperature. To the cooled mixture were added25 mL of water and 20 mL of acetone, and the organic liquid portion wasseparated. The organic liquid portion was washed with a saturatedaqueous sodium chloride solution and dried over anhydrous magnesiumsulfate. The dry organic liquid portion was filtered and concentratedunder reduced pressure. The residue was crystallized from heptane, toobtain 6.58 g of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesulfonylamino)pyrimidineas a pale yellow crystalline product. The yield was 86% (based on theamount of4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).

EXAMPLE 8 Preparation of4-(4-fluorophenyl)-6-isoproply-5-methoxycarbonyl-2-(N-methyl-N-methanesulfonyl-amino)pyrimidine

In a 1000 mL-volume glass flask equipped with a stirrer, a thermometerand a reflux condenser were placed 50.0 g (172 mmol.) of4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine,20.8 g (189 mmol.) of sodium t-pentoxide, and 344 mL of acetonitrile,and the resulting mixture was stirred at 0-10° C. for 30 minutes. To themixture was slowly added 36.1 g (189 mmol.) of p-toluenesulfonylchloride, and the reaction was carried out at for 5 hours at roomtemperature. Subsequently, the reaction mixture was cooled to atemperature of 0-10° C. To the cooled reaction mixture were added 28.2 g(258 mmol.) of N-methylmethanesulfonamide and 26.5 g (241 mmol.) ofsodium t-pentoxide. The mixture was kept at 0-10° C. for one hour andthen heated to 75-82° C. for 2 hours under refluxing, to carry out areaction. After the reaction was complete, the mixture was cooled toroom temperature. To the cooled mixture was added 344 mL of water. Theaqueous mixture was cooled to 0-10° C. and stirred for one hour,precipitating a crystalline product. The crystalline product wascollected by filtration and dried, to obtain 45.3 g of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesulfonylamino)pyrimidineas a pale yellow crystalline product. The yield was 68% (based on theamount of4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).

EXAMPLE 9 Preparation of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesulfonylamino)pyrimidinefrom methyl isobutyrylacetate, 4-fluorobenzaldehyde and urea

1) In a 200 L-volume glass-lined reaction vessel equipped with astirrer, a thermometer and a reflux condenser were placed 24.4 kg (169mol.) of methyl isobutyrylacetate, 20.0 kg (161 mol.) of4-fluorobenzaldehyde, 16.9 kg (282 mol.) of urea, 0.2 kg (2 mol.) ofcopper(I) chloride, 3.0 kg of sulfuric acid, and 80.4 kg of methanol.The mixture was heated to 64-66° C. for 20 hours under refluxing, tocarry out reaction. After the reaction was complete, the reactionmixture was cooled to room temperature, to precipitate a crystallineproduct. The crystalline product was collected on a filter paper andwashed with methanol to obtain 43.4 kg of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-3,4-2(1H)-dihydropyrimidinoneas a colorless crystalline product.

2) In a 200 L-volume glass-lined reaction vessel equipped with a stirrerand a thermometer were placed 62.5 kg (615.6 mol.) of diluted nitricacid and 0.5 kg (6.8 mol.) of sodium nitrite. To the mixture was slowlyadded under chilling 20.0 kg (68.4 mmol.) of the4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-3,4-2(1H)-dihydropyrimidinoneprepared as above. The resulting mixture was subjected to reaction at alow temperature (10° C.). After the reaction was complete, the reactionmixture was neutralized by addition of an aqueous methanol solution ofsodium hydroxide. Subsequently, an aqueous sodium hydroxide solution wasadded to the mixture. The resulting mixture was placed under reducedpressure to distill methanol off. To the residue were added 96.5 kg ofacetone and 96.5 kg of water. The aqueous residue was then neutralizedby addition of acetic acid to precipitate a crystalline product. Thecrystalline product was collected on a filter paper and washed with aacetone/water mixture, to give 17.9 kg of4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine.

3) In a 200 L-volume glass-lined reaction vessel equipped with astirrer, a thermometer and a reflux condenser were placed 17.9 kg (62.0mol.) of4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidineprepared as above, 107.7 kg of butyl acetate, 11.1 kg (80.3 mol.) ofpotassium carbonate (available from Asahi Glass Works, Co., Ltd., LotNo. 1111632, particle size distribution: 75-250 μm: 14%, 75 μm pass:86%), and 12.9 kg (67.7 mol.) of p-toluenesulfonyl chloride. The mixturewas heated at 60° C. for 2 hours, to carry out reaction. Subsequently,the reaction mixture was cooled to room temperature. To the cooledmixture were added 8.8 kg (80.6 mol.) of N-methylmethanesulfonamide and12.9 kg (93.3 mol.) of potassium carbonate, and the resulting mixturewas heated at 122-125° C. for 3 hours, for carrying reaction. After thereaction was complete, the reaction mixture was cooled to roomtemperature. To the cooled mixture were added acetone and water, and theorganic liquid portion was separated. The organic liquid portion wasthen washed successively with aqueous sodium hydroxide solution (3 wt.%) and a saturated aqueous sodium chloride solution. The washed organicliquid portion was concentrated under reduced pressure. Isopropylalcohol and water were added to the residue, resulting in precipitationof a crystalline product. The crystalline product was filtered on afilter paper and washed with isopropyl alcohol. The washed crystallineproduct and 85.7 kg of acetone were placed in a 200 L-volume glass linedreaction vessel equipped with a stirrer, a thermometer and a refluxcondenser. The mixture was stirred at 50-55° C., to dissolve thecrystalline product in acetone. The insoluble was removed with a linefilter. Subsequently, 58.3 kg of water was added to the solution, toprecipitate a crystalline product. The crystalline product was collectedon a filter paper and washed with an acetone/water mixture, to give 19.5kg of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesulfonylamino)pyrimidine.

EXAMPLE 10 Preparation of2-chloro-4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonylpyrimidine

In a 25 mL-volume glass flask equipped with a stirrer, a thermometer anda reflux condenser were placed 1.00 g (3.43 mmol.) of4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine and3.4 mL (3.7 mmol.) of phosphorus oxychloride. The mixture was heated to100-106° C. for 1.5 hours under refluxing, to carry out reaction. Afterthe reaction was complete, the reaction mixture was cooled to roomtemperature, and poured into an ice/water mixture. The resulting aqueousmixture was neutralized with a saturated aqueous sodium hydrogencarbonate solution. The neutralized aqueous mixture was extracted withethyl acetate. The ethyl acetate portion was separated, washed with asaturated aqueous sodium chloride solution, and dried over anhydrousmagnesium sulfate. The dried ethyl acetate portion was filtered andconcentrated under reduced pressure, to obtain 1.03 g of2-chloro-4-(4-fluorophenyl)-6-isopropyl-5-methoxy-carbonylpyrimidine asa colorless crystalline product having the below-mentionedcharacteristics. The yield was 97% (based on the amount of4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).

m.p.: 99-101° C.

UV λ_(max) (CH₃CN, nm): 194.7, 276.5

IR (KBr, cm⁻¹): 2980, 1728, 1542, 1508, 1227, 1086.

¹H-NMR (DMSO-d₆, δ (ppm)): 1.33 (6H, d, J=6.8 Hz), 3.1-3.2 (1H, m), 3.76(3H, s), 7.15 (2H, t, J=8.5 Hz), 7.6-7.7 (2H, m).

HRMS: 308.0695 (theoretical value (C₁₅H₁₄ClFN₂O₂ (M+)) 308.0728)

EXAMPLE 11 Preparation of2-chloro-4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonylpyrimidine

In a 25 mL-volume glass flask equipped with a stirrer, a thermometer anda reflux condenser were placed 1.00 g (3.43 mmol.) of4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine,0.5 mL (3.9 mmol.) of thionyl chloride, 3.44 mL of toluene, and 0.11 mLof N,N-dimethylformamide. The mixture was heated to 80° C. for 3 hours,to carry out reaction. After the reaction was complete, the reactionmixture was cooled to room temperature, and poured into an ice/watermixture. The resulting aqueous mixture was neutralized with a saturatedaqueous sodium hydrogen carbonate solution. The neutralized aqueousmixture was extracted with ethyl acetate. The ethyl acetate portion wasseparated, washed with a saturated aqueous sodium chloride solution, anddried over anhydrous magnesium sulfate. The dried ethyl acetate portionwas filtered and concentrated under reduced pressure, to obtain 0.80 gof 2-chloro-4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonylpyrimidineas a colorless crystalline product. The yield was 76% (based on theamount of4-(4-fluorophenyl)-2-hydroxy-6-isoproply-5-methoxycarbonylpyrimidine).

EXAMPLE 12 Preparation of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesulfonyl-amino)pyrimidine

In a 25 mL-volume glass flask equipped with a stirrer, a thermometer anda reflux condenser were placed 546 mg (5 mmol.) ofN-methylmethanesulfonamide, 551 mg (5 mmol.) of sodium t-pentoxide, 10mL of acetonitrile, and 309 mg (1 mmol.) of2-chloro-4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonylpyrimidine. Themixture was heated to 81-82° C. for 3 hours under refluxing, to carryout reaction. After the reaction was complete, the reaction mixture wascooled to room temperature. To the cooled mixture was added 10 mL ofwater, and the aqueous mixture was extracted with ethyl acetate. Theethyl acetate portion was separated, and dried over anhydrous magnesiumsulfate. The dried ethyl acetate portion was filtered and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (column: Wako Gel C-200, eluent: hexane/ethyl acetate(2:1, volume ratio)). There was obtained 339 mg of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesulfonylamino)pyrimidine.The yield was 89% (based on the amount of2-chloro-4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonylpyrimidine).

EXAMPLE 13 Preparation of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-methanesulfonyloxypyrimidine

In a 100 mL-volume glass flask were placed 10.0 g (34.4 mmol.) of4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine,5.22 g (58.5 mmol.) of triethylamine, and 34 mL of acetonitrile. Themixture in the flask was chilled to 0-5° C. in an ice bath. To thechilled mixture was slowly added 5.12 g (44.7 mmol.) of methanesulfonylchloride, and the resulting mixture was subjected to reaction at 20-25°C. for 2 hours. After the reaction was complete, to the reaction mixturewas added 60 mL of water. The aqueous reaction mixture was extractedwith toluene and the toluene portion was separated. The toluene portionwas washed with a saturated aqueous sodium chloride solution and driedover anhydrous magnesium sulfate. The dried mixture was filtered andconcentrated under reduced pressure. The residue was crystallized frommethanol, to give 11.3 g of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-methanesulfonyloxypyrimidineas a colorless crystalline product having the below-mentionedcharacteristics. The yield was 89% (based on the amount of4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).

m.p.: 110-111° C.

UV λ_(max) (CH₃CN, nm): 193.7, 276.8

IR (KBr, cm⁻¹): 2980, 1724, 1562, 1391, 1250, 1175, 1079, 971.

¹H-NMR (CDCl₃, δ (ppm)): 1.33 (6H, d, J=6.6 Hz), 3.20 (1H, m), 3.60 (3H,s), 7.1-7.2 (2H, s), 7.6-7.8 (2H, m).

HRMS: 368.0842 (theoretical value (C₁₅H₁₇FN₂O₅S(M+)) 368.0892)

EXAMPLE 14 Preparation of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(p-toluenesulfonyloxy)pyrimidine

In a 200 mL-volume glass flask were placed 27.6 g (95.1 mmol.) of4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine,12.5 g (123 mmol.) of triethylamine, and 95 mL of acetonitrile. Themixture of the flask was chilled to 0-5° C. in an ice bath. To thechilled mixture was slowly added 20.0 g (105 mmol.) of p-toluenesulfonylchloride, and the resulting mixture was subjected to reaction at 20-25°C. for one hour. After the reaction was complete, to the reactionmixture was added 95 mL of water. The aqueous reaction mixture wasextracted with toluene and the toluene portion was separated. Thetoluene portion was washed with a saturated aqueous sodium chloridesolution and dried over anhydrous magnesium sulfate. The dried mixturewas filtered and concentrated under reduced pressure. The residue wascrystallized from methanol, to give 35.9 g of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(p-toluenesulfonyloxy)pyrimidineas a colorless crystalline product having the below-mentionedcharacteristics. The yield was 85% (based on the amount of4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).

m.p.: 94-96° C.

UV λ_(max) (CH₃CN, nm): 194.9, 275.2

IR (KBr, cm⁻¹): 2961, 1734, 1539, 1389, 1352, 1247, 1090, 980.

¹H-NMR (CDCl₃, δ (ppm)): 1.23 (6H, d, J=6.8 Hz), 2.45 (3H, s), 3.0-3.2(1H, m), 3.74 J=8.5 Hz).

HRMS: 444.1155 (theoretical value (C₂₂H₂₁FN₂O₅S(M+)) 444.1194)

EXAMPLE 15 Preparation of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-benzenesulfonyloxypyrimidine

The procedures of Example 13 were repeated except for replacingp-toluenesulfonyl chloride with 18.5 g (105 mmol.) of benzenesulfonylchloride.

There was obtained 39.3 g of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-benzenesulfonyloxypyrimidineas a pale yellow crystalline product having the below-mentionedcharacteristics. The yield was 96% (based on the amount of4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).

¹H-NMR (CDCl₃, δ (ppm)): 1.21 (6H, d, J=6.4 Hz), 3.0-3.1 (1H, m), 3.73(3H, s), 7.1-7.2 (2H, m), 7.5-7.7 (5H, m), 8.1-8.2 (2H, m).

EXAMPLE 16 Preparation of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(2,4,6-trimethylbenzenesulfonyloxy)pyrimidine

The procedures of Example 13 were repeated except for replacingp-toluenesulfonyl chloride with 23.0 g (105 mmol.) of2,4,6-trimethylbenzenesulfonyl chloride.

There was obtained 37.7 g of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(2,4,6-trimethylbenzenesulfonyloxy)pyrimidineas a pale yellow crystalline product having the below-mentionedcharacteristics. The yield was 84% (based on the amount of4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).

¹H-NMR (CDCl₃, δ (ppm)): 1.17 (6H, d, J=6.8 Hz), 2.34 (3H, s), 2.67 (6H,s), 3.0-3.1 (1H, m), 3.73 (3H, s), 7.00 (2H, s), 7.0-7.2 (2H, m),7.4-7.5 (2H, m).

EXAMPLE 17 Preparation of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(2,4,6-triisopropylbenzenesulfonyloxy)pyrimidine

The procedures of Example 13 were repeated except for replacingp-toluenesulfonyl chloride with 31.8 g (105 mmol.) of2,4,6-triisopropylbenzenesulfonyl chloride.

There was obtained 47.1 g of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(2,4,6-triisopropylbenzenesulfonyloxy)pyrimidineas a pale yellow crystalline product having the below-mentionedcharacteristics. The yield was 89% (based on the amount of4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).

¹H-NMR (CDCl₃, δ (ppm)): 1.12 (6H, d, J=6.6 Hz), 1.19 (12H, d, J=6.8Hz), 1.27 (6H, d, J=7.1 Hz), 2.8-2.95 (1H, m), 2.95-3.1 (1H, m), 3.73(3H, s), 4.1-4.3 (2H, m), 7.0-7.1 (2H, m), 7.20 (2H, s), 7.4-7.5 (2H,m).

EXAMPLE 18 Preparation of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(p-methoxybenzenesulfonyloxy)-pyrimidine

The procedures of Example 13 were repeated except for replacingp-toluenesulfonyl chloride with 21.7 g (105 mmol.) ofp-methoxybenzenesulfonyl chloride.

There was obtained 39.9 g of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(p-methoxybenzenesulfonyloxy)pyrimidineas a colorless crystalline product having the below-mentionedcharacteristics. The yield was 91% (based on the amount of4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).

¹H-NMR (CDCl₃, δ (ppm)): 1.25 (6H, d, J=6.8 Hz), 3.0-3.2 (1H, m), 3.74(3H, s), 3.88 (3H, s), 6.99 (2H, dd, J=2.0, 9.0 Hz), 7.0-7.2 (2H, m),7.5-7.7 (2H, m), 8.07 (2H, dd, J=2.2, 9.0 Hz).

EXAMPLE 19 Preparation of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(p-chlorobenzenesulfonyloxy)-pyrimidine

The procedures of Example 13 were repeated except for replacingp-toluenesulfonyl chloride with 22.2 g (105 mmol.) ofp-chlorobenzenesulfonyl chloride.

There was obtained 39.9 g of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(p-chlorobenzenesulfonyloxy)pyrimidineas a colorless crystalline product having the below-mentionedcharacteristics. The yield was 89% (based on the amount of4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).

¹H-NMR (CDCl₃, δ (ppm)): 1.23 (6H, d, J=6.6 Hz), 3.0-3.2 (1H, m), 3.74(3H, s), 7.1-7.2 (2H, m), 7.5-7.7 (4H, m), 8.0-8.1 (2H, m).

EXAMPLE 20 Preparation of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(2-nitrobenzenesulfonyloxy)-pyrimidine

The procedures of Example 13 were repeated except for replacingp-toluenesulfonyl chloride with 23.3 g (105 mmol.) of2-nitrobenzenesulfonyl chloride.

There was obtained 28.0 g of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(2-nitrobenzenesulfonyloxy)pyrimidineas an opaque crystalline product having the below-mentionedcharacteristics. The yield was 62% (based on the amount of4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).

¹H-NMR (CDCl₃, δ (ppm)): 1.17 (6H, d, J=6.8 Hz), 3.0-3.2 (1H, m), 3.75(3H, s), 7.1-7.2 (2H, m), 7.5-7.6 (2H, m), 7.7-8.0 (3H, m), 8.33 (1H,dd, J=1.7, 8.1 Hz).

EXAMPLE 21 Preparation of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesulfonylamino)pyrimidine

In a 25 mL-volume glass flask equipped with a stirrer, a thermometer anda reflux condenser were placed 196 mg (1.8 mmol.) ofN-methylmethanesulfonamide, 198 mg (1.8 mmol.) of sodium t-pentoxide,7.5 mL of acetonitrile, and 667 mg (1.5 mmol.) of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(p-toluenesulfonyloxy)pyrimidine.The mixture was heated to 81-82° C. for 1.5 hours under refluxing, tocarry out reaction. After the reaction was complete, the reactionmixture was cooled to room temperature. To the cooled mixture was added10 mL of water, and the aqueous mixture was extracted with ethylacetate. The ethyl acetate portion was separated, and dried overanhydrous magnesium sulfate. The dried ethyl acetate portion wasfiltered and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (column: Wako Gel C-200,eluent: hexane/ethyl acetate (2:1, volume ratio)). There was obtained428 mg of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesulfonylamino)-pyrimidine.The yield was 75% (based on the amount of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(p-toluenesulfonyloxy)pyrimidine).

EXAMPLE 22 Preparation of(2-amino-4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonylpyrimidine

In a 25 mL-volume glass flask equipped with a stirrer, a thermometer anda gas inlet were placed under ice-chilling 1.00 g (2.71 mmol.) of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-methanesulfonyloxypyrimidineand 8.1 mL of tetrahydrofuran. The mixture was stirred at roomtemperature for 12 hours under gaseous ammonia atmosphere, for carryingout reaction. After the reaction was complete, 10 mL of water was addedto the reaction mixture. The aqueuos mixture was then subjected toextraction with toluene. The toluene portion was separated, washed witha saturated aqueous sodium chloride solution, and dried over anhydrousmagnesium sulfate. The dried toluene portion was filtered andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (column: Wako Gel C-200, eluent: hexane/ethylacetate (2:1, volume ratio)). There was obtained 0.63 g of2-amino-4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonylpyrimidine. Theyield was 80% (based on the amount of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-methanesulfonyloxypyrimidine).6-isopropyl-5-methoxycarbonylpyrimidine

EXAMPLE 23 Preparation of(4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-N-methylaminopyrimidine

In a 50 mL-volume glass flask equipped with a stirrer, a thermometer anda dropping funnel was placed 6.00 g (16.3 mmol.) of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-methanesulfonyloxypyrimidine.Into the flask was slowly dropped under ice-chilling 5.06 g (65.2 mmol)of aqueous 40 wt. % methylamine solution. The resulting mixture wasstirred for one hour at the same temperature for carrying out reaction.After the reaction was complete, 16 mL of water was added to thereaction mixture. The aqueuos mixture was then subjected to extractionwith toluene. The toluene portion was separated, washed with a saturatedaqueous sodium chloride solution, and dried over anhydrous magnesiumsulfate. The dried toluene portion was filtered and concentrated underreduced pressure to give 4.81 g of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-N-methylaminopyrimidine.The yield was 97% (based on the amount of4-(4-fluoro-phenyl)-6-isopropyl-5-methoxycarbonyl-2-methanesulfonyloxypyrimidine).

EXAMPLE 24 Preparation of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-trifluoromethanesulfonyloxypyrimidine

In a 300 mL-volume glass flask equipped with a stirrer, a thermometerand a reflux condenser were placed 8.7 g (30.0 mmol.) of4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine,3.0 g (30.0 mmol.) of triethylamine, and 150 mL of toluene. The mixturein the flask was chilled to 0° C. in an ice bath. To the chilled mixturewas slowly added 8.46 g (30.0 mmol.) of trifluoromethanesulfonicanhydride, and the resulting mixture was subjected to reaction for 3hours at the same temperature. After the reaction was complete, to thereaction mixture was added 90 mL of water. From the aqueous reactionmixture, an organic liquid portion was separated. The organic liquidportion was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (column: Wako Gel C-200,eluent: hexane/ethyl acetate (8:2, volume ratio)). There was obtained8.46 g of4-(4-fluorophenyl)-6-isoproply-5-methoxycarbonyl-2-trifluoromethanesulfonyloxypyrimidinehaving the below-mentioned characteristics as a colorless oil. The yieldwas 74% (based on the amount of4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).

IR (KBr, cm⁻¹): 3421, 2978, 1737, 1570, 1429, 1222, 1136, 973, 851

¹H-NMR (CDCl₃, δ (ppm)): 1.33 (6H, d, J=6.6 Hz), 3.1-3.2(1H, m), 3.80(3H, s), 7.1-7.2 (2H, m), 7.7-7.8 (2H, m)

HRMS: 422.0585 (theoretical value (C₁₆H₁₄F₄N₂O₅S(M+)) 422.0560)

EXAMPLE 25 Preparation of4-(4-flurophenyl)-6-isopropyl-5-methoxycarbonyl-2-trifluoromethanesulfonyloxypyrimidine

In a 300 mL-volume glass flask equipped with a stirrer, a thermometerand a reflux condenser were placed 2.9 g (10.0 mmol.) of4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine,1.7 g (16.8 mmol.) of triethylamine, and 50 mL of toluene. The mixturein the flask was chilled to 0° C. in an ice bath. To the chilled mixturewas slowly added 2.4 g (14.1 mmol.) of trifluoromethanesulfonylchloride, and the resulting mixture was subjected to reaction for 3hours at the same temperature. After the reaction was complete, to thereaction mixture was added 30 mL of water. From the aqueous reactionmixture, an organic liquid portion was separated. The organic liquidportion was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (column: Wako Gel C-200,eluent: hexane/ethyl acetate (8:2, volume ratio)). There was obtained2.8 g of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-trifluoromethanesulfonyloxypyrimidinehaving the below-mentioned characteristics as a colorless oil. The yieldwas 66% (based on the amount of4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).

EXAMPLE 26 Preparation of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesulfonylamino)pyrimidine

In a 50 mL-volume glass flask equipped with a stirrer, a thermometer anda reflux condenser were placed 3.0 g (7 mmol.) of4-(4-fluorophenyl-6-isopropyl-5-methoxycarbonyl-2-trifluoromethanesulfonyloxypyrimidine,1.13 g (10.5 mmol.) of N-methylmethanesulfonamide, 1.45 g (10.5 mmol.)of potassium carbonate (available from Wako Junyaku Co., Ltd., specialgrade), and 14 mL of butyl acetate. The mixture was heated to 122-125°C. for 3 hours under refluxing, to carry out reaction. After thereaction was complete, the reaction mixture was cooled to roomtemperature. To the reaction mixture were added 10 mL of water and 7 mLof acetone, and the organic liquid portion was separated. The organicliquid portion was washed with a saturated aqueous sodium chloridesolution and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (column: Wako Gel C-200,eluent: hexane/ethyl acetate (5:1, volume ratio)). There was obtained2.1 g of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesulfonylamino)pyrimidineas a white crystalline product. The yield was 78% (based on the amountof4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-trifluoromethanesulfonyloxypyrimidine).

EXAMPLE 27 Preparation of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesulfonylamino)pyrimidine

In a 50 mL-volume glass flask equipped with a stirrer, a thermometer anda reflux condenser were placed 1.1 g (2.5 mmol.) of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(p-toluenesulfonyloxy)pyrimidine,0.55 g (5.0 mmol.) of N-methylmethanesulfonamide, 0.69 g (5.0 mmol.) ofpotassium carbonate (available from Wako Junyaku Co., Ltd., specialgrade), 0.32 g (1.0 mmol.) of tetrabutylammonium bromide, 20 mL oftoluene and 5 mL of water. The mixture was heated to 85° C. for 28 hoursunder refluxing, to carry out reaction. After the reaction was complete,the reaction mixture was cooled to room temperature. To the reactionmixture were added 10 mL of water and 7 mL of acetone, and the organicliquid portion was separated. The organic liquid portion was analyzed byhigh performance liquid chromatography. It was confirmed that 0.6 g of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesulfonylamino)pyrimidinewas produced. The yield was 63% (based on the amount of4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(p-toluenesulfonyloxy)pyrimidine).

INDUSTRIAL UTILITY

The pyrimidine compound, particularly,2-(N-methyl-N-methanesulfonylamino)pyrimidine compound, prepared by theinvention is of value as an intermediate compound for the production ofa cholesterol reducing agent (HMG-CoA reductase agent). The compound offormula (3) can be converted to an HMG CoA reductase inhibitor by theprocesses disclosed in European Patent Application Publication No.0521471, Bioorg. Med. Chem., 5, 437 (1997) and International PatentApplication No. WO 00/49014. The disclosures of these references areincorporated herein by reference to demonstrate how a compound offormula (3) or formula (8) can be converted to an HMG CoA reductaseinhibitor, in particular, rosuvastatin or a pharmaceutically acceptablesalt thereof, such as rosuvastatin calcium.

1. A hydroxypyrimidine compound having the formula (1):

in which R is selected from the group consisting of an alkyl grouphaving 1 to 10 carbon atoms, a cycloalkyl group having 3 to 6 carbonatoms, an aryl-alkyl group having an alkyl moiety of 1 to 3 carbon atomsan aryl group and a methylphenyl group.
 2. The hydroxypyrimidinecompound of claim 1, wherein R is an alkyl group having 1 to 10 carbonatoms, a cycloalkyl group having 3 to 6 carbon atoms, an aryl-alkylgroup having an alkyl moiety of 1 to 3 carbon atoms, or an aryl group.3. A method for preparing the hydroxypyrimidine compound of claim 1,which comprises oxidizing a dihydropyrimidinone compound having theformula (4):

wherein R is selected from the group consisting of an alkyl group having1 to 10 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, anaryl-alkyl group having an alkyl moiety of 1 to 3 carbon atoms an arylgroup and a methylphenyl group.
 4. The method of claim 3, wherein thedihydropyrimidinone compound is oxidized using nitric acid.
 5. Themethod of claim 3, wherein the dihydropyrimidinone compound is preparedby reacting an isobutyrylacetate ester having the formula (5):

in which R is the same as defined in claim 3, with 4-fluorobenzaldehydeand urea in the presence of a protonic compound selected from the groupconsisting of an inorganic acid or its salt, an organic sulfonic acid,an organic carboxylic acid and an alcohol; and a metal salt selectedfrom the group consisting of copper(I) chloride, copper(II) chloride,copper(II) acetate, iron(II) chloride, iron(III) chloride, aluminumchloride, nickel(II) bromide, tin(IV) chloride, titanium tetrachlorideand magnesium bromide.
 6. The method of claim 5, wherein the protoniccompound is a protonic acid.
 7. The method of claim 6, wherein theprotonic acid is sulfuric acid.
 8. The method of claim 5, wherein themetal salt is copper(I) chloride.